RRx-001 + Radiation + Temozolomide In Newly Diagnosed Glioblastoma and Anaplastic Gliomas

Glioblastoma multiforme also known by the feared three letter acronym or abbreviation, GBM,
is the most common, aggressive and deadly type of brain tumor, which is standardly treated
with a combination of radiation and temozolomide (TMZ), an FDA approved chemotherapy agent,
followed by temozolomide alone. One of the reasons why glioblastoma is so aggressive and
deadly has to do with poor blood flow: it turns out that GBM has multiple inefficient and
leaky blood vessels, which leads to ineffective and irregular delivery of nutrients and
oxygen to the tumor.

As illogical as it may sound at first, depriving cancer cells of the oxygen and vital
nutrients that they need to grow actually makes them more (not less as might be expected)
aggressive and harder to treat.

Here's why: for radiation to have an effect on the tumor oxygen is required since the
combination of oxygen and radiation produces unstable and highly reactive free radicals;
these microscopic free radicals are the equivalent of a spray of bullets, which ricochet or
bounce around violently inside the tumor producing catastrophic damage.

Likewise, for chemotherapy such as TMZ to work it has to reach the tumor and when blood
vessels are so abnormal that the blood practically ceases to flow the TMZ, for example, may
either never actually get there or may arrive in such small quantities that it is
ineffective.

The expression "survival of the fittest" also applies: under the poorly oxygenated harsh
conditions, which result from this sluggish blood flow only the toughest and most resistant
cancer cells survive, making the tumor that much harder to eliminate with traditional
therapies.

Think of the blood flow to the tumor as a swamp or a marsh where the rotten water seeps and
pools rather than flows and where only the hardiest organisms can compete for scarce
resources and low oxygen, which partly explains why this GBM tumor type in particular is
often so hard to treat.

This clinical trial, called G-FORCE-1, tests the safety, tolerability and activity of
RRx-001, an experimental anticancer agent, with standard radiation and temozolomide followed
by temozolomide + RRx-001 in newly diagnosed GBM. Evidence in animals and in human patients
with brain metastases, that is cancer cells, which have metastasized or spread to the brain
from different locations in the body, has shown that RRx-001, which has many anticancer
mechanisms and is generally very well tolerated both alone and in combination with radiation
in other clinical trials, increases blood flow to tumors.

The increased blood flow has three possible beneficial consequences: 1) more oxygen is
delivered to the tumor, which has the potential to increase the activity of radiation 2) more
TMZ makes it to the tumor, which has the potential to increase the activity of TMZ and 3) as
conditions in the tumor gradually improve from intolerable or barely tolerable to more
acceptable, treatment sensitive cancer cells may start to reappear.

RRx-001 is also thought to work by stimulating the immune system to attack the tumor; tumor
biopsies or samples from patients in other RRx-001 trials have demonstrated the infiltration
or penetration of a particular kind of white cell called T-cells. As a fourth potentially
beneficial consequence of the increased blood flow from RRx-001, these immune T-cells may
have better access to the tumor, which may, in turn, increase killing of the cancer cells.

G-FORCE-1 is a Phase 1 trial, which means that the main endpoint is to test the safety and
tolerability of RRx-001 in combination with radiation and temozolomide and not its activity;
however patients will be followed for responses to treatment and overall survival

Inclusion Criteria:

- Histologically proven diagnosis of high-grade glioma, including anaplastic glioma (WHO
grade III with 1p/19q chromosomes intact), glioblastoma (WHO grade IV) or gliosarcoma
(WHO Grade IV);

- The tumor must not have an infratentorial component;

- The patient must have recovered from the effects of surgery, postoperative infection
and other complications before enrollment;

- Estimated survival of at least 12 weeks;

- Karnofsky Performance Score of ≥ 70% at the time of entry

- Stable or decreasing steroid dose within 2 weeks of first dose of study drug if
patient is taking steroids. No steroid use is also acceptable.

- Neurological stability for at least 14 days prior to first dose of study drug;

- Acceptable liver function at Screening,

- Serum creatinine < 1.5x institution upper limit of normal

- Acceptable hematologic status at Screening

- Female subjects of childbearing potential, and male subjects with partners of
childbearing potential, must agree to use medically acceptable methods of
contraception.

Exclusion Criteria:

- Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease
free for ≥ 3 years.

- Recurrent malignant gliomas previously treated with radiotherapy and/or chemotherapy

- Metastases detected below the tentorium or beyond the cranial vault, including tumors
with evidence of leptomeningeal metastases as previously indicated;

- Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note
that prior chemotherapy for a different cancer is allowable, except prior
temozolomide. Prior use of Gliadel wafers or any other intratumoral or intracavitary
treatment are not permitted;

- Prior radiotherapy to the head or neck (except for T1 glottic cancer), that would
result in overlap of radiation fields.

- Active connective tissue disorders, such as lupus or scleroderma that in the opinion
of the treating physician may put the patient at high risk for radiation toxicity;

- Unresolved toxicity higher than CTCAE (v. 4.03) Grade 1 attributed to any prior
therapy/procedure excluding alopecia and hypothyroidism;

- Acquired immune deficiency syndrome (AIDS) due to the potential for increased
complications from treatment; note, however, that HIV testing is not required

- No other concurrent chemotherapeutic or investigational agents for this cancer.
However, concurrent glucocorticoids are allowed;

- Inability to swallow pills;

- Serious co-morbid medical conditions, or a clinically significant laboratory
finding(s) or any finding(s) on history and/or examination that, in the opinion of the
Investigator, could interfere with the conduct of the study or could put the patient
at unacceptable risk;

- Patients who are pregnant or lactating or who are planning to become pregnant during
the course of the study are excluded.